Project Summary Hepatitis B virus (HBV) infection is a major global health problem, resulting in progressive liver disease, including cirrhosis and hepatocellular carcinoma. While current therapies control infection, viral cure is rarely achieved. Using a liver cell-based system of HBV infection combined with single cell profiling, we aim to unravel the host cell responses to hepatitis B virus infection in individual cells enabling to discover key drivers of transcriptional reprogramming by the virus. More specifically, leveraging spatial and temporal profiling, we aim to obtain a comprehensive overview of the impact of the virus on the transcriptomic patterns of hepatocytes, including host responses to viral infection and modulation of host factors involved required for the HBV life cycle and immune evasion. Using state-of-the-art techniques for the integrative analysis of single cell and time course gene expression profiles, we expect to emerge with several discrete host targets that represent candidates for the design of small molecule therapeutics for cure of infection. We hypothesize that our integrative analysis will allow us to decipher unexplored virus-host interactions of particular interest for the development of viral curative strategies.